US2023263817A1PendingUtilityA1

High dose nicotinamide adenine dinucleotide (nad) precursor regimens for reduction of inflammation in human patients with preexisting inflammation

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Assignee: UNIV WASHINGTONPriority: Aug 28, 2020Filed: Aug 27, 2021Published: Aug 24, 2023
Est. expiryAug 28, 2040(~14.1 yrs left)· nominal 20-yr term from priority
Inventors:Rong TianDennis Ding-Hwa WangBo ZhouKevin O'Brien
A61K 31/706G01N 33/6869G01N 33/5094A61P 29/00G01N 2333/5412G01N 2333/545G01N 2800/325G01N 2800/7095A61K 31/7048G01N 33/5055G01N 33/5091G01N 2800/52C07H 19/048
53
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Claims

Abstract

The current disclosure provides use of high dose nicotinamide adenine dinucleotide (NAD) precursor regimens for reduction of inflammation in human patients with preexisting inflammation. The NAD precursor can be nicotinamide riboside (NR) and the high dose regimen can include at least 1000 or 2000 mg/day for at least 9 days.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A method comprising:
 identifying a human Stage D heart failure patient;   orally administering to the human Stage D heart failure patient 2000 mg/day of nicotinamide riboside (NR), wherein the 2000 mg/day is split into two 1000 mg/day doses;   obtaining peripheral blood mononuclear cells (PBMCs) from the human Stage D heart failure patient;   measuring the oxygen consumption rate (OCR) of the obtained PBMCs; and   measuring the expression level of interleukin (IL)6, IL1β, and IL18 by the obtained PBMCs.   
     
     
         2 . The method of  claim 1 , wherein the orally administering is for 9 consecutive days. 
     
     
         3 . The method of  claim 1 , wherein the identified human Stage D heart failure patient is hospitalized. 
     
     
         4 . A method comprising:
 identifying a human subject with a preexisting inflammation marker profile; and   orally administering a high dose regimen of a nicotinamide adenine dinucleotide (NAD) precursor to the human subject,
 wherein the high dose regimen of the NAD precursor reduces inflammation markers in the human subject's peripheral blood mononuclear cells (PBMCs). 
   
     
     
         5 . The method of  claim 4 , wherein the preexisting inflammation marker profile is based on an assessment of the human subject's PBMCs expression level of an inflammatory marker. 
     
     
         6 . The method of  claim 5 , wherein the inflammatory marker is NLRP3. 
     
     
         7 . The method of  claim 6 , wherein the PBMC's NLRP3 expression level is higher than a baseline level. 
     
     
         8 . The method of  claim 5 , wherein the inflammatory marker is IL6. 
     
     
         9 . The method of  claim 8 , wherein the PBMC's IL6 expression level is higher than 6 pg/mL. 
     
     
         10 . The method of  claim 5 , wherein the inflammatory marker is IL1β. 
     
     
         11 . The method of  claim 10 , wherein the PBMC's IL1β expression level is higher than 1.0 pg/mL. 
     
     
         12 . The method of  claim 5 , wherein the inflammatory marker is IL18. 
     
     
         13 . The method of  claim 12 , wherein the PBMC's IL18 expression level is higher than 492 pg/mL. 
     
     
         14 . The method of  claim 5 , wherein the inflammatory marker is TNFα. 
     
     
         15 . The method of  claim 14 , wherein the PBMC's TNFα expression level is higher than 1 pg/mL. 
     
     
         16 . The method of  claim 5 , wherein the inflammatory marker is NLRP3, IL6, IL1β, IL18, and TNFα. 
     
     
         17 . The method of  claim 16 , wherein the PBMC's NLRP3 expression level is higher than a baseline level, the IL6 expression level is higher than 6 pg/mL, the PBMC's IL1β expression level is higher than 1.0 pg/mL, the PBMC's IL18 expression level is higher than 492 pg/mL, and the PBMC's TNFα expression level is higher than 1 pg/mL. 
     
     
         18 . The method of  claim 4 , wherein the reduced inflammation marker in the human subject's PBMCs is an increase in the PBMC's oxygen consumption rate as compared to the PBMC's oxygen consumption rate before administering the high dose regimen. 
     
     
         19 . The method of  claim 4 , wherein the reduced inflammation marker in the human subject's PBMCs is a decrease in the PBMC's NLRP3 expression level as compared to the PBMC's NLRP3 expression level before administering the high dose regimen. 
     
     
         20 . The method of  claim 4 , wherein the reduced inflammation marker in the human subject's PBMCs is a decrease in the PBMC's IL6 expression level as compared to the PBMC's IL6 expression level before administering the high dose regimen. 
     
     
         21 . The method of  claim 4 , wherein the reduced inflammation marker in the human subject's PBMCs is a decrease in the PBMC's IL1β expression level as compared to the PBMC's IL1β expression level before administering the high dose regimen. 
     
     
         22 . The method of  claim 4 , wherein the reduced inflammation marker in the human subject's PBMCs is a decrease in the PBMC's IL18 expression level as compared to the PBMC's IL18 expression level before administering the high dose regimen. 
     
     
         23 . The method of  claim 4 , wherein the reduced inflammation marker in the human subject's PBMCs is a decrease in the PBMC's TNFα expression level as compared to the PBMC's TNFα expression level before administering the high dose regimen. 
     
     
         24 . The method of  claim 4 , wherein the reduced inflammation marker in the human subject's PBMCs is an increase in the PBMC's oxygen consumption rate, and a decrease in the PBMC's expression of NLRP3, IL6, IL1β, IL18, and TNFα as compared to the PBMC's oxygen consumption rate, and NLRP3, IL6, IL1β, IL18, and TNFα expression level before administering the high dose regimen. 
     
     
         25 . The method of  claim 4 , wherein the high dose regimen comprises a dose of the NAD precursor of at least 1000 mg/day. 
     
     
         26 . The method of  claim 4 , wherein the high dose regimen comprises a dose of the NAD precursor of at least 2000 mg/day. 
     
     
         27 . The method of  claim 26 , wherein the high dose regimen comprises the 2000 mg/day dose for at least 5 days, for at least 9 days, for at least 12 days, or for at least 12 weeks. 
     
     
         28 . The method of  claim 4 , wherein the NAD precursor is nicotinamide riboside (NR). 
     
     
         29 . The method of  claim 4 , wherein the NAD precursor is an NR analogue comprising NRH triacetate, NRH triproprionate, NRH tributyrate, NRH triisobutyrate, NR+ tripentanoate, NR+ trihexanoate, NRH triethylcarbonate, NRH tribenzoate, NR+ monohexanoate, NRH monodecanoate, NRH monotetradecanoate, Nic mononucleotide (NMN), NR+ monooleate, NR+ monohexanoate, NR+ monononanoate, NR+ monododecanoate, NR+ monopentanoate, or NR+ monoundecanoate. 
     
     
         30 . The method of  claim 4 , wherein the NAD precursor is NR chloride or a crystalline form of NR chloride. 
     
     
         31 . The method of  claim 30 , wherein the crystalline form of NR chloride comprises
 3-carbamoyl-1-((2R,3R,4S,5R)-3,4-dihydroxy-5(hydroxymethy)tetrahydrofuran-2-yl)pyridin-1-ium(β-D-NR) chloride crystal,   3-carbamoyl-1-((2R,3R,4S,5R)-3,4-dihydroxy-5(hydroxymethy)tetrahydrofuran-2-yl)pyridin-1-ium(β-D-NR chloride methanolate crystal, or   3-carbamoyl-1-((2S,3R,4S,5R)-3,4-dihydroxy-5(hydroxymethyl)tetra hydrofuran-2-yl)pyridin-1-ium chloride.   
     
     
         32 . The method of  claim 4 , wherein the NAD precursor is an NR analogue comprising O-ethyl NR (OENR), tri-O-acetyl O′-ethyl NR (TAENR), N-dimethyl NR (DMNR), or N-allyl NR (ANR). 
     
     
         33 . The method of  claim 4 , wherein the human subject with the preexisting inflammation marker profile has a heart condition, an autoimmune disease, cancer, diabetes, a chronic respiratory disease, stroke, obesity, or allergies. 
     
     
         34 . The method of  claim 33 , wherein the heart condition is Stage A, B, C, or D heart failure. 
     
     
         35 . The method of  claim 34 , wherein the heart condition is Stage D heart failure. 
     
     
         36 . The method of  claim 33 , wherein the autoimmune disease is lupus or rheumatoid arthritis. 
     
     
         37 . A composition comprising at least 1000 mg of a NAD precursor. 
     
     
         38 . The composition of  claim 37 , comprising 2000 mg of a NAD precursor. 
     
     
         39 . The composition of  claim 37 , wherein the NAD precursor is NR. 
     
     
         40 . The composition of  claim 37 , wherein the NAD precursor is an NR analogue comprising NRH triacetate, NRH triproprionate, NRH tributyrate, NRH triisobutyrate, NR+ tripentanoate, NR+ trihexanoate, NRH triethylcarbonate, NRH tribenzoate, NR+ monohexanoate, NRH monodecanoate, NRH monotetradecanoate, Nic mononucleotide (NMN), NR+ monooleate, NR+ monohexanoate, NR+ monononanoate, NR+ monododecanoate, NR+ monopentanoate, or NR+ monoundecanoate. 
     
     
         41 . The composition of  claim 37 , wherein the NAD precursor is NR chloride or a crystalline form of NR chloride. 
     
     
         42 . The composition of  claim 37 , wherein the crystalline form of NR chloride comprises
 3-carbamoyl-1-((2R,3R,4S,5R)-3,4-dihydroxy-5(hydroxymethy)tetrahydrofuran-2-yl)pyridin-1-ium(β-D-NR) chloride crystal,   3-carbamoyl-1-((2R,3R,4S,5R)-3,4-dihydroxy-5(hydroxymethy)tetrahydrofuran-2-yl)pyridin-1-ium(β-D-NR chloride methanolate crystal, or   3-carbamoyl-1-((2S,3R,4S,5R)-3,4-dihydroxy-5(hydroxymethyl)tetra hydrofuran-2-yl)pyridin-1-ium chloride.   
     
     
         43 . The composition of  claim 37 , wherein the NAD precursor is an NR analogue comprising O-ethyl NR (OENR), tri-O-acetyl O′-ethyl NR (TAENR), N-dimethyl NR (DMNR), or N-allyl NR (ANR).

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